The prompt and accurate initiation of drug therapy to a patient is essential in the treatment of many medical conditions. An inappropriate dosage regimen may produce therapeutic failure as the result of subtherapeutic drug levels or, alternatively, due to toxic drug levels (overdose). Determining therapeutic dosage is often complicated by the therapeutic index of a drug. In clinical medicine, the therapeutic index of a drug is the ratio of the highest potentially therapeutic concentration to the lowest potentially therapeutic concentration. Thus, therapeutic index defines the acceptable range of blood serum concentration for an individual drug. As used herein, the term "therapeutic" when used in connection with "drug dosage," "drug dosage regimen" and "concentration," etc. shall be defined, without limiting its customary meaning, as the appropriate drug dosage necessary to provide a desired effect without producing concomitant adverse affects.
Many drugs, such as aminoglycosides, theophylline, gentamicin, and lithium, have narrow therapeutic ranges. The proper administration of these drugs requires an accurate prediction of the relationship between dose, dosing interval and the resulting blood concentration of the drug in the patient. "Recommended dosage" information is often provided by a drug manufacturer or is available from a drug compendium or the like. for some drugs, this information is sufficient such that no further predictive determination is necessary. In these instances, the recommended dosage is simply administered without further consideration of serum concentrations. However, when it is necessary to initiate drug therapy using one or more drugs having narrow therapeutic ranges, such as aminoglycosides, establishing a therapeutic dosage regimen is quite complex.
To assist the medical team in making this determination, various predictive methods have been developed by others in the past for calculating an appropriate dose and dose interval for drug administration. Due to inherent inaccuracies of prior art methods, it has been held that an appropriate dosage regimen should be derived cautiously where possible by administering a loading dose and then developing a dosage regimen slowly by raising serum concentrations until satisfactory results are obtained. As those skilled in the art will appreciate, however, a conservative exploration of therapeutic drug levels is not always possible and aggressive drug therapy is often necessary. This is particularly true for gram negative infections where the first 24 hours of treatment may be critical.
It will be understood by those skilled in the art that the dosage regimen includes the quantity of drug administered (dose) and the frequency of administration (dosing interval). It will also be appreciated that various methods of drug delivery are available such as intravenous or intraperitoneal injection or the like and that often drugs will be introduced by infusion. The dosing profile of a drug is determined by its pharmacokinetic characteristics.
The initiation of drug therapy includes the administration of an initial loading dose and subsequent interim maintenance doses at periodic intervals to achieve therapeutic "peak" and "trough" blood concentrations. In conventional methods, a determination of the dosage regimen typically involves the use of nomograms and dosing guidelines derived from population averages. Typically, measured serum drug concentrations will not be available before a maintenance dose is required.
Prior art predictive dosing methods for aminoglycoside antibiotics include the dosing chart of Sarubbi-Hull, the dosing technique of Dettli, the dosing nomogram of Chan and the Rule of Eights. In general, these methods utilize the patient's weight to estimate volume of distribution (V). Creatinine clearance is calculated from the patient's serum creatinine level to estimate an elimination rate constant (K). The use of K and V in drug dosage determination will be well-known to those of average skill in the art. Some methodologies employ ideal body weight while others utilize actual body weight. It will be understood by those in the art, that in reality each patient exhibits a singular ability to eliminate a drug (K) and a characteristic drug volume of distribution (V) for a particular drug. Hence the values of both K and V for a patient may deviate significantly from population-based averages. It has been shown by others that these conventional methods result in subtherapeutic and potentially toxic blood concentrations in many patients when used for the administration of certain drugs. In particular, it is known that nomograms and dosing guidelines are poor predictors of the elimination rate constant (K). Hence, there is a need for a more accurate method for predicting drug serum concentration such that therapeutic dosing can be achieved during initial drug therapy.
Following the initiation of drug therapy, blood assays are typically performed to determine analytically the serum concentration of the therapeutic agent. New values for K and V are then derived using the serum drug concentration data. Dosage adjustment is then effected as needed, based on the new values of K and V. Although this method of drug dosage adjustment is preferable over continued use of unindividualized predictive dosing determinations, blood analysis suffers from several drawbacks. Repeated venupuncture, which is generally used to obtain a blood sample, may cause patient discomfort with an associated risk of nosocomial infection. Also, the frequency of blood sampling may require periodic transfusions to prevent anemia.
An additional factor which militates against the use of blood assays to determine dosage regimen is the cost associated with blood analysis. In order to obtain blood data, a physicians order must be prepared pursuant to which a trained phlebotomist must draw the blood sample. The sample is then carefully labeled with identifying information and sent to a laboratory for testing. Laboratory technicians must then separate and isolate the blood serum through centrifugation or the like. Utilizing a variety of analytical methods, the serum concentration of the drug is then determined usually in duplicate to enhance the accuracy of the testing procedure. This information must then be conveyed to the medical team so that it can be used to evaluate and adjust the dosing regimen. It has been estimated that the cost of analyzing a single blood specimen in a hospital may exceed one hundred dollars.
Moreover, and serving to further impede dosage determination, the data obtained from the blood assay may be meaningless for a number of reasons. It will be appreciated by those skilled in the art that blood assaying is a complex and laborious task. It has been estimated that up to 40% of all blood samples analyzed for serum drug concentration yield data which cannot be used to determine an appropriate dosage regimen. Therefore, it would be desirable to provide an inexpensive method for determining a dosage regimen which can be performed without complicated assays or highly skilled technicians. To that end, we have discovered an inexpensive method of determining dosage requirements which provides accurate, individualized dosing data by noninvasive means.